The present cost of treating inflammatory diseases around the world is huge. Often these diseases may persist in patients for weeks or months (chronic inflammation) requiring extended and costly care. Chronic inflammation may be described as that of a long duration in which active inflammation, tissue destruction and attempts at healing proceed simultaneously (see Robbins Pathological Basis of Disease by R. S. Cotran, V. Kumar and S. L. Robbins, W. B. Saunders Co., p75, 1989). Sometimes, inflammatory diseases will start as acute episodes (causing pain and economic loss to the patient) and develop into chronic inflammatory conditions with subsequent dehabilitating consequences to both the mental and physical well-being of the patient. Despite these severe consequences, there are often few therapeutic options for patients with chronic inflammatory diseases such as arthritis, restenosis, psoriasis, multiple sclerosis, surgical adhesions, inflammatory bowel diseases and chronic inflammatory lung diseases. Often patients are treated temporarily with steroidal or non-steroidal anti-inflammatories to relieve the symptoms of the diseases but these therapies offer little long-term benefit and are associated with serious side effects if used too frequently (such as gastric ulcers from non-steroidal anti-inflammatories or more serious toxicities from steroidal abuse).
Clearly, there exists a great need for compounds (and effective methods of delivery) that may treat these diseases more effectively. The complex and multifaceted nature of inflammatory diseases indicates that agents with singular molecular mechanisms of action may not be candidates to achieve such therapeutic objectives.
Arthritis
Rheumatoid arthritis (RA) is a debilitating chronic inflammatory disease characterized by pain, swelling, synovial cell proliferation (pannus formation) and destruction of joint tissue. In the advanced stage, the disease often damages critical organs and may be fatal. The disease involves multiple members of the immune system (macrophages/monocytes, neutrophils, B cells and T cells) complex cytokine interactions and synovial cell malfunction and proliferation. Early aggressive treatment is now recommended with disease modifying anti-rheumatic drugs (DMARDS) such as methotrexate and combinations with cyclosporin or azathioprine (see Arthritis and Rheumatism 39(5):713-722. 1996).
Crystal induced arthritis is characterized by crystal induced activation of macrophages and neutrophils in the joints and is followed by excruciating pain for many days. The disease progresses so that the intervals between episodes gets shorter and morbidity for the patient increase to unacceptable levels. This disease is generally treated symptomatically with non-steroidal anti-flammatory drugs (NSAIDs) (see McCarty et al in Arthritis and Allied Conditions by Lea and Febiger, Philadelphia 1495, 1985).
Restenosis
Restenosis is a form of chronic vascular injury leading to vessel wall thickening and loss of blood flow to the tissue supplied by the blood vessel. This inflammatory disease occurs in response to vascular reconstructive procedures including any manipulation that relieves vessel obstruction and is thus the major restrictive factor limiting the effectiveness of these procedures. At present, there are no approved treatments for the prevention of restenosis in humans. Systemic therapies such as aspirin, calcium channel blockers, heparin, steroids or colchicine have shown poor results in the treatment of this disease.
Inflammatory Bowel Disease (IBD)
This disease refers mainly to Krohn's disease and ulcerative colitis that affect the intestine. IBD is an inflammatory disease characterized by periods of flare and remission. Joint inflammation may occur at the same time as a flare of IBD. Other complications of IBD may include inflammation of the skin, mouth, eye and may lead to cancer of the intestine. Chronic symptoms of these disease include intestinal blockage, perforation, abscess and bleeding and may be treated by surgical removal of the diseased area.
The cause of IBD remains unknown. In ulcerative colitis, there is an inflammatory reaction in the colonic mucosa leading to ulcer formation. Neutrophil infiltration is common and repeated inflammatory episodes may lead to fibrosis and ultimately cancer. Krohn's disease is characterized by chronic inflammation associated with macrophages and neutrophils in the intestine. As the disease progresses, the bowel thickens and stenosis of the lumen may occur followed by ulceration. There are no truly effective pharmacological treatments for IBD. Symptoms may be relived with steroidal or non-steroidal anti-inflammatory agents such as corticosteroids or aminosalicylates.
Chronic Inflammatory Lung Diseases
These inflammatory diseases include asthma, pneumoconiosis, obstructive pulmonary disease, nasal polyps and pulmonary fibrosis. Typically, such diseases are characterized by immune cell (such as neutrophils, macrophages and lymphocytes) activation and invasive inflammatory processes and thickening of the affected masses. For example Polyps are characterized by thickened tissue of the nasal lining. Current drug therapies generally involve the use of steroidal and non-steroidal anti-inflammatory agents to treat inflammatory symptoms.
Chronic Inflammatory Skin Diseases.(e.g. Psoriasis or Eczema)
Psoriasis is a common, chronic inflammatory skin disease characterized by raised, thickened and scaly lesions which itch, burn, sting and bleed easily. While these diseases have cellular proliferation and angiogenic components in later stages of the disease, patients often have accompanying arthritic conditions. Treatments targeted specifically to just cellular proliferation or angiogenesis are not likely to be effective in treating this disease. The cause of the disease is unknown and there is no cure for the disease at present.
The disease is characterized by neutrophil accumulation and activation, cell proliferation and angiogenesis, illustrating the complex multi-component nature of this inflammatory disease. Skin cells, may follow two routes of growth, normal growth or wound healing. In normal growth, cells are created in the basal layer and move up through the epidermis to the skin surface. Dead cells are shed from the surface at the same rate as new ones form below. During wound healing, accelerated growth and repair is triggered resulting in rapid turnover of skin cells, increased blood supply and inflammation. In some respects psoriasis is an exaggerated wound healing process. If the skin does not shed the skin cells (keratinocytes) as quickly as they are made then a build up may occur. This may lead to scaly lesions and angiogenesis (to increase the blood supply). At the same time, lymphocytes, neutrophils and macrophages may invade the area and create soreness, swelling and inflammation. Current drug therapies generally involve the use of steroidal and non-steroidal anti-inflammatory agents to treat inflammatory symptoms. Methotrexate and cyclosporin are also used with marginal efficacy.
Surgical Adhesions
Surgical adhesion formation is a complex inflammatory disease in which tissues that normally remain separated in the body grow into each other, usually as a result of surgical trauma. These adhesions are a major cause of failed surgical procedures and are the leading cause of bowel obstruction and infertility. Other adhesion related complications include chronic pelvic pain, urethral obstruction and voiding dysfunction. Inflammatory processes include neutrophil accumulation and activation in the traumatized tissues, fibrin deposition and bonding of adjacent tissues, macrophage invasion, fibroblast proliferation into the area, collagen deposition, angiogenesis and the establishment of permanent adhesion tissues. Current therapies include prevention of fibrin deposition, reduction of inflammation (steroidal and non-steroidal anti-inflammatory drugs) and removal of fibrin deposits. All these methods are ineffective in reducing the severity of adhesion formation and treatments specifically targeted at only the cellular proliferation or angiogenic facets of this disease are not expected to be effective.
Multiple Sclerosis (MS)
This disease is the most common inflammatory disease of the nervous system. Almost half of patients progress from having mild impairment of cognitive function and loss of nervous function to a more chronic phase of crippling the patient due to loss of visual activity, disturbed motor function such as walking, incontinence and sensory defects. Therapeutics recently approved for use against MS include interferon-B (Paty et al., Neurology 43:662-667) which improves quality of life but does not affect disease progression. Hunter et al. (PCT application published under WO/98/24427) proposes that anti-microtubule agents such as paclitaxel inhibit MS progression. The exact mechanism of action of this drug in treating these diseases in unknown since paclitaxel not only stabilizes microtubules but it also inhibits central signalling factors involved in inflammatory diseases such as MAPkinase (Jackson J. K. et al in Immunology 1997, (90) p502-510) and AP1 (Hui A. et al Arthritis and rheumatism, 41(5) p 869-876 1998.).
MS is characterized by demyelination of the nervous system and consequent disruption of nervous messages around the body. As the disease progresses, there is a progressive demyelination in the brain associated with immune cell activity around the nerves and astrocyte proliferation on the nerve. Phagocytic macrophages are active around the nerve with increased oxygen radical production, protease secretion and myelin breakdown. It has been reported that macrophages/monocytes from MS patients are in an “alerted” or primed, semi-activated state and oversecrete oxygen radicals and proteases that may destroy myelin (see Fisher et al. Inflammation 12 (2) 123-31 1998 or Podikoglou et al. Neurology 44 (1) 129-132 1994.), and that neutrophils from MS patients bind tumor necrosis factor-alpha (a common priming cytokine in MS) more strongly than neutrophils from non-MS patients indicating involvement of neutrophils in the progression of MS (Ziaber. J. et al. Journal of Investigational Allergology and Clinical Immunology. 10(2):98-101 2000). A more detailed study showed that during MS exacerbation and in the course of chronic progressive MS, neutrophils express increased numbers of pro-inflammatory cell markers (Zieber et al. Mediators in Inflammation 7(5):335-8 1998). Inhibition of neutrophil and macrophage oxygen radical and protease function offers one strategy for suppressing myelin damage. Another therapeutic approach is promotion of programmed cell death (apoptosis) in neutrophils as a way of preventing the accumulation of these cells around the nerve.
The PCT application published under WO 98/24427 describes therapeutic applications of anti-microtubule agents. Included in this publication is data indicating that such anti-microtubule activity is also exhibited by camptothecin, for example in inhibition of restenosis and for inhibition of angiogenesis. Camptothecin is also known as a topoisomerase I inhibitor and has use in cancer therapy as an anti-viral agent and as a radiosensitizing agent (Takimoto, C. H. et al (1998) Biochemica et Biophysica Acta, 1400:107-119; and, Wang, D. S. et al (1996) Biol. Pharm. Bull. 19:354-359). Camptothecin has also been proposed for possible use against the cellular proliferation aspect of psoriasis (see: Lin, X. R. et al (1998) Int. J. Dermatology 27(7):475-476). Prior to this invention, there was no indication that inflammatory disease may be treated by inhibition of topoisomerases.